Voltage-gated sodium (Nav) channels are present in neurons and excitable tissues where they contribute to processes such as membrane excitability and muscle contraction (Ogata et al., Jpn. J. Pharmacol. (2002) 88(4), 365-77). Nine different transmembrane β-subunits (Nav1.1-1.9) from a single Nav1 family combine with auxiliary β-subunits that modify channel function to form functional Nav channels. Of the nine Nav1 β-subunit isoforms, five are expressed in the dorsal root ganglion where they are involved in setting the resting membrane potential and the threshold for generating action potentials, and also contribute to the upstroke as well as firing of action potentials during sustained depolarization. In particular, the tetrodotoxin (TTX) sensitive Nav1.7 and TTX-insensitive Nav1.8 channel subtypes act as major contributors to both inflammatory and neuropathic pain (Momin et al., Curr. Opin. Neurobiol. 18(4):383-8, 2008; Rush et al., J. Physiol. 579(Pt 1):1-14, 2007).
Pathological pain states induce neuronal hyper-excitability in the peripheral and central nervous systems and as a consequence modulate voltage-gated ion channel behavior (Coderre and Katz, Behav. Brain Sci. 20(3):404-19, 1997; Hildebrand et al., Pain. 152(4):833-843, 2011). In humans, gain-of-function mutations in the Nav1.7 gene, SNC9A, yield the condition of inherited erythromelalgia typified by extreme pain, redness and swelling in the extremities (Drenth and Waxman, J. Clin. Invest. 117(12):3603-3609, 2007). These mutations result in amino acid substitutions that alter channel function and induce hyper-excitability of the Nav1.7 channel by allowing the ion channel to open at lower membrane potentials (Cheng et al., Mol. Pain. 4(1):1-9, 2008). Across the various Nav1.7 mutations identified as contributing to erythromelalgia, select mutations result in a reduction of pain severity (Cheng et al., Brain. 134(Pt 7):1972-1986, 2011). While these mutations still allow the channel to open at lower membrane potentials, this subset alters the manner in which the ion channel resets to its original closed state so that it can continue to participate in pain signaling. While unmutated Nav1.7 channels reset primarily through a kinetically rapid state on the millisecond timescale (fast-inactivation), erythromelalgia mutations resulting in less pain promote channel resetting through a kinetically slow state on the second time scale (slow-inactivation). By limiting channel availability and further participation in sodium ion gating, enhanced entry into the slow-inactivated state reduces pain signaling.
Novel allosteric modulators of voltage-gated ion channels, e.g., voltage gated sodium channels, are thus desired to promote therapeutic analgesia. Modulators may affect the kinetics and/or the voltage potentials of, e.g., Nav1.7 or Nav1.8, channels. In particular, modulators that affect the state-dependence of voltage gated sodium channels by enhancing entry in the slow-inactivated state may be of particular utility in limiting pain signaling by limiting channel availability.